Methamphetamine (MA) dependence is associated with neuropsychiatric side effects that make the addiction extremely challenging to treat. Patients seeking treatment experience ongoing impairments in cognition, mood, and motivation. Currently, there are no FDA-approved pharmacotherapies for MA dependence. The goal of this proof-of-concept research project is test whether or not immunotherapy using recombinant T-cell receptor ligands (RTLs) can be used to regulate glia-derived and related immune factors, concurrently triggering healing responses in the brain and improving MA-induced cognitive impairment. Our rationale for this novel treatment approach is the increasing body of evidence which demonstrates that neuroimmune factors contribute to MA-induced neuronal injury and cognitive impairment. Yet, the question of whether or not autoimmune disease and drug addiction have common mechanistic factors has only recently been asked. Based on current support in the literature and our own findings, it is postulated that MA alters blood brain barrier permeability thereby exposing central nervous system (CNS) antigens [e.g., myelin oligodendrocyte glycoprotein (MOG)] and facilitating the development of anti-CNS responses. Thus, the central hypothesis to be tested with this project is that RTLs can promote brain healing following MA use by reducing immunoreactivity to neuronatigens, preventing further neurodegeneration, and allowing for myelin repair. The Specific Aims intended to test this hypothesis include: 1) evaluate the therapeutic efficacy of RTL551 (comprised of the distal ss1+11 domains of the mouse I-Ab class II molecule linked covalently to MOG-35-55 peptide) in improving cognitive function in mice following chronic MA use, and 2) determine if RTL551 modulation of the inflammatory activity of CNS antigen reactive T lymphocytes results in decreased neuronal degeneration and increased white matter repair. Methods: Following chronic MA versus saline administration, mice will be treated with RTL versus vehicle. Mice will undergo cognitive behavioral testing and brain sample collection following the drug and intervention treatment phases. The Novel Object Recognition Task and the Morris Water Maze will be used to measure cognitive functioning, and immunohistochemistry will be used to detect CNS indicators of neuronal degeneration and myelin repair. We hypothesize that RTL551 treatment will reduce cognitive deficits and improve CNS repair in MA-treated mice. In line with NIDA's mission to support research that will improve drug abuse treatment, the long-term objective of this research program is to discover, develop, and test agents that will safely and effectively treat neuropsychiatric impairments and repair neuronal injury following addiction. Thus, in Phase II of this program, we will propose a series of preliminary safety and toxicity experiments in order to begin preclinical testing of RTLs for patients with MA addiction. The results from our preclinical trial will potentially offer a new treatment strategy for MA dependence and abuse. PUBLIC HEALTH RELEVANCE: Methamphetamine (MA) addiction is a growing epidemic in our nation, yet there are no FDA-approved medications to treat MA dependence. Chronic MA abuse is known to cause neuronal injury and neuroanatomical changes that are associated with cognitive impairments and the cognitive impairments that persist during recovery likely contribute to high relapse rates and poor treatment outcomes. Therefore, discovery of an immunotherapy that could improve brain repair and cognitive recovery following MA addiction would represent a major scientific breakthrough that could broadly impact addiction treatment and outcomes.